DESCRIPTION: (Adapted from the Applicant's Description) Craniofacial anomalies, and in particular, clefts of the lip and palate, are important contributors to the morbidity associated with birth defects. Clefts have a Complex etiology that involves both genes and gene-environmental influences. Their frequency varies across populations of different geographic origins, but averages about 1 in 700 live births and results in the need for surgical, speech, psychological, dental and cosmetic interventions. In this proposal, the investigators will take advantage of a pre-existing population of biological samples and environmental data on two large collections from the United States and the Philippines to look for gene-environment etiologies. They will use a highly selected collection of a large number (200) of candidate genes chosen for their role in craniofacial development based on expression data and animal model studies. One hundred of these candidate genes will undergo complete sequence analysis for 200 cases of cleft lip and palate. In parallel analysis, the investigators will work with the Cancer Genome Anatomy Project Genetic Annotation Initiative to validate and confirm 100 additional variants identified through their efforts to study genes that play a role in development and xenobiotic transformations. Variants identified in the sequence analysis and the Genetic Annotation Initiative will then be studied using linkage disequilibrium and gene-environment analytic strategies for the role that they might play in cleft lip and palate. The statistical analysis will take advantage of a primary collection of 300 nuclear triads (mother, father, affected child) on which TDT and related analyses can be carried out. Significant findings can be validated using samples available by collaboration with the CDC National Birth Defects Prevention Programs. A technology development component will evaluate the efficiencies of genotyping by comparing a current laboratory standard single strand conformational variant (SSCV) analysis to two more automatable fluorescence quenching approaches molecular beacon and Taqman analysis. Finally, the investigators will choose a subset of SNP variants identified from the 200 genes studied for characterization on the 1,000 member CEPH Diversity Panel. This 1,000 member set of DNA samples from individuals whose geographic origins represent the entire globe will provide an opportunity to characterize useful gene variants for a group of investigators wishing to study the role of those variants in other disorders, such as cancer or birth defects. The outcome of this project will be the characterization of a large number of genetic variants that play a role in development and xenobiotic transformation, as they relate to clefts and a set of tools for extension to studies of other developmental abnormalities.